Throughout this application, various references are cited in square brackets to describe more fully the state of the art to which this invention pertains.
Hyaluronan (HA, an anionic polymer of repeating units of glucuronic acid and N-acetylglucosamine) is one extracellular matrix (ECM) component of stroma, that is associated with cancer progression: increased accumulation of tumor HA is prognostic of poor outcome in cancer patients [1, 2, 3]. HA stimulates cancer cell motility in vitro, suggesting its importance in cancer cell invasion in vivo. Two HA cellular receptors that have been implicated in cancer progression are CD44 and RHAMM (receptor for HA-mediated motility).
Progenitor or “tumour initiating cells” are now generally accepted to disproportionately contribute to the tumour forming potential of leukemias. A similar phenomenon has more recently been described in breast cancer (BC) and other solid tumours and the phenotype of these tumour cell subsets has been partially characterized as CD44+/CD24−/ESA+. Although the precise relationship of these cell subsets to clinical outcome is controversial, CD44+ cells sorted by FACS from primary BC express a gene signature that predicts poor clinical outcome. RHAMM mRNA and protein hyper-expression also occur in primary human breast tumour cell subsets and the presence of these RHAMM positive subsets is predictive of poor clinical outcome and increased risk of peripheral metastasis in BC. Although CD44 is expressed in many normal tissues, RHAMM expression is not detected in these tissues but appears following wound repair and during pathological processes such as cancer progression. Imaging of CD44-positive and RHAMM-positive tumour cell subsets would therefore be relevant in identifying patients at risk for poor outcome. However, as to the date of this document these and/or other tumour progenitor cells have not yet been directly imaged. It would, therefore, be advantageous to find a molecular imaging probe capable of targeting RHAMM to provide a means of imaging progenitor cell status non-invasively. This targeting method could also provide a method of selectively targeting progenitor cells with a therapeutic drug agent, either directly through the ligand-receptor interaction, or indirectly by delivering a therapeutic payload to the targeted cells. For example, one could deliver particle emitting isotopes to the progenitor cells, or could deliver a chemotherapeutic to the cells (eg. Cisplatin). The present invention provides for novel peptide ligands for targeting RHAMM, which has not been previously reported.